Numerous clinical conditions are associated with excessive constriction of one or more vascular beds. These include hypertension, angina pectoris and peripheral vascular disease all of which predispose to myocardial infarction, stroke and heart failure and erectile dysfunction. The healthcare and socioeconomic consequences of cardiovascular disease are staggering. According to World Health Organisation (WHO) estimates, 16.7 million people worldwide died of cardiovascular disease in 2003 which amounts to some 29% of all death globally. 80% of such deaths occur in low and middle income countries and account for more than 5 times the total number of deaths due to HIV/AIDS in these countries (American Heart Association, 2007). In economic terms, it has been estimated that cardiovascular disease costs every European Union (EU) citizen 230 Euros/year in healthcare and accounts for 268.8 million lost working days. Furthermore, at any one time approximately 600 million individuals globally suffer from hypertension and estimates suggest that this number will rise to 1.56 billion in 2025. Angina pectoris is also common and affected more than 6 million people in the USA in 2004 with a further 400,000 new cases diagnosed each year (Parker J. O. (2004) Am. J. Geriatric Cardiology, 13, 261-266). This number is expected to double by 2030. Other examples of cardiovascular disease include peripheral vascular disease which afflicts over 27 million people in Europe and North America (Belch J J, et al. (2003) Arch Int. Med., 163, 884-892). Finally, the incidence of erectile dysfunction globally is also rising from 152 million in 1995 to an estimated 322 million in 2025 (Aytak™, M., Krane, R. J. (1999) BJI Int., 84, 50-56).
The incidence of each of these cardiovascular disease states is rising perhaps as the population lives longer. Existing drug therapy for these conditions is based largely on the use of drugs which either directly or indirectly elicit vasodilation. These include, amongst others, Ca++ channel antagonists, angiotensin converting enzyme inhibitors, sympatholytics and diuretics. However, the ever increasing incidence of these diseases is testimony to the fact that currently available drugs are not able “to stem the tide” and it is generally recognized that such treatments are inadequate.
The need for new vasodilator agents with novel mechanisms of action is clear.